Protein Is Linked to Prostate Cancer

By NATALIE ANGIER

Published: July 1, 1992

Researchers have discovered the likely reason prostate cancer so often spreads into the backbone, an event that is usually a prelude to death from the disease. They have found that bone tissue is rich in a protein that sharply stimulates the growth of prostate tumor cells.

The new work suggests that advanced prostate cancer may be amenable to treatment by blocking the activity of the stimulatory protein, a molecule called transferrin. It also casts light on the grim puzzle of metastasis, the mechanism through which a rebel cell wrests free of a primary tumor and sets up lethal outposts elsewhere in the body.

Dr. Marcella Chackal Rossi of the Massachusetts Institute of Technology in Cambridge and Dr. Bruce R. Zetter of Children's Hospital in Boston report their results today in The Proceedings of the National Academy of Sciences.

"This is a very interesting and encouraging finding," said Dr. William G. Stetler-Stevenson, who studies cancer metastasis at the National Cancer Institute in Bethesda, Md. "The fact that prostate cancers frequently spread to the bone is a significant clinical problem, and it's important to understand the specific factors that facilitate the metastasis. Transferrin seems to be one of them." Rapid Growth in Backbone

Long dismissed as an old man's tumor and relatively neglected by many researchers, prostate cancer has lately captured wide attention among scientists and the public alike. The malignancy afflicts a pecan-sized gland located at the base of the bladder that generates fluids to help nourish and transport sperm.

Prostate cancer is the second most common cause of cancer deaths among men; this year, about 125,000 men will contract the malignancy, and about 32,000 who already suffer from the disease will die of it. Often they will die because the malignancy has spread from the gland to the bones of the spine. When confined to the prostate, the malignancy grows slowly, taking decades to reach a diameter smaller than that of a pencil eraser. But scientists have found that once it moves to the bone, its growth explodes, and death usually follows within five years.

In the new work, the researchers set out to determine what it is about bone that hastens the growth of prostate cancer cells. They knew that any tumor cells escaping from the prostate could reach the spine through blood vessels traveling into it. But they wanted to know why the cells thrived so malevolently in the bone once they infiltrated it. "It's not enough for the circulation to bring the cells somewhere," said Dr. Zetter. "The site has to be suitable for the growth of the secondary tumor."

To find the factors that encourage the renegade cells, the researchers separated components from bone marrow and searched for proteins that hastened the proliferation of prostatic tumor cells growing in laboratory dishes. That method yielded the isolation of transferrin, a protein that abounds throughout the body but is particularly concentrated in the bone. Wheelbarrow and Fertilizer

In its normal guise, transferrin helps to deliver iron into the body's cells, clasping onto trace bits of the metal floating in the bloodstream and ferrying it into the cell's yolk-like interior, where the iron can perform tasks like fostering enzymatic reactions. The protein seems necessary in bone marrow to help in blood cell performance. "Red blood cells carry iron and need iron, so it's thought that one reason for the high concentration of transferrin in bone marrow is to allow red blood cell formation," said Dr. Zetter.

The new results strongly suggest that beyond serving as a molecular wheelbarrow, transferrin can behave as a potent growth factor, kindling cell division. "There's been some dispute about whether transferrin is just a passive iron transporter, or whether it's also a growth factor in its own right," said Dr. George J. Todaro of the Fred Hutchinson Cancer Center in Seattle. "It does seem here to be a critical growth factor for prostate cancer."

But transferrin does not always stimulate tumor growth. The scientists tested other types of metastatic cancer cells, including samples from breast, stomach and lung malignancies, to see whether they responded to the iron-bearing protein; none did.

The researchers also propose that there may even be differences between prostate tumors. Some tumor cells may have a heightened avidity for transferrin because they bear extra receptors on their surface that can detect the protein, while other tumors may not be overendowed with receptors and thus be less likely to spread. New Avenue for Therapy

"We hope that some of these findings will lead to the ability to distinguish between prostatic tumors that are highly metastatic, and those that will stay in the prostate," said Dr. Zetter.

The work also may also lead to better therapies for prostate cancer. Currently, tumors that are confined to the gland are surgically removed or destroyed with radiation. Once the malignancy spreads, it can be held in abeyance with drugs that block male hormones, but the treatment almost inevitably fails. Researchers hope that they may eventually be able to control advanced prostate cancer by stanching its access to transferrin, perhaps designing antibodies that prevent the cells from responding to the protein.

But scientists do not yet know whether they can cut off the transferrin pipeline to prostate cancer cells without depriving the rest of the body of the critical delivery protein. "It's possible that if you were to block transferrin at sufficiently high levels" to affect the cancer, said Dr. Todaro, "you'd have some very serious side effects."